Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity.
Model cell lines developed from MCF7 breast carcinoma cells were used to examine the roles of glutathione S-transferase P1-1 (GSTP1-1) and multidrug resistance protein (MRP) in the protection of cells from 4-nitroquinoline 1-oxide (4NQO) toxicities. Increased expression of GSTP1-1 alone in MCF7 cells results in limited protection from the formation of 4NQO-derived covalent adducts of nucleic acids but affords no protection from 4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formation and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO-SG) conjugate formation and a MRP-dependent increase in QO-SG efflux. These data indicate that MRP is an important export transporter for the glutathione conjugate of the carcinogen, 4NQO. Moreover, this MRP-dependent efflux activity is necessary to achieve the full protection from 4NQO toxicity-protection that is potentiated by GSTP1-1-mediated QO-SG formation.
Morrow
C S
CS
Department of Biochemistry, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1016, USA. cmorrow@bgsm.edu
Diah
S
S
Smitherman
P K
PK
Schneider
E
E
Townsend
A J
AJ
D015112:4-Nitroquinoline-1-oxide / Q000493:pharmacokinetics* / Q000633:toxicity*; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D001943:Breast Neoplasms; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis; D007700:Kinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured
D015112:4-Nitroquinoline-1-oxide; D018528:ATP-Binding Cassette Transporters; D002273:Carcinogens; D005978:Glutathione; D005982:Glutathione Transferase; D007527:Isoenzymes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011994:Recombinant Proteins